Pharmacology: Insomnia Drugs and Treatments

Pharmacology: Insomnia

• Insomnia is defined as dissatisfaction with sleep quality or quantity, plus one or more of the following:
  • Difficulty falling asleep (sleep onset).
  • Difficulty staying asleep (sleep maintenance).
  • Early morning awakening without being able to return to sleep.

Lecture Competencies

• Compare and contrast the mechanisms of action, indications, and adverse effects of drugs to treat insomnia (with and without comorbidities).
  • Benzodiazepines (e.g., Temazepam).
  • Benzodiazepine receptor agonists (Z-drugs) (e.g., Zopiclone).
  • Dual orexin receptor antagonists (e.g., Lemborexant).
  • Tricyclic antidepressants (e.g., Doxepin).
• Discuss drugs often used off-label for comorbid insomnia.
• Discuss pharmacotherapeutic options for children.
• Discuss pharmacotherapeutic options for the elderly.
• Discuss pharmacotherapeutic options for use during pregnancy and breastfeeding.
• Prescribe appropriate medications for people with insomnia based on patient history.

Goals of Therapy

• Improve daytime function.
• Reduce daytime impairment (e.g., dysphoria, fatigue, decreased alertness).
• Promote subjectively sound and restorative sleep.
• Potentiate the effectiveness of behavioural interventions.

Medications Contributing to Insomnia

• Antidepressants
• Stimulants
• Antihypertensives
• Sedatives
• Decongestants and antihistamines
• Analgesics
• Herbal supplements
• Substances of abuse

Insomnia with Comorbidity

• Many people with insomnia have other conditions that contribute to their sleep problems.
  • Musculoskeletal conditions.
  • Psychiatric disorders.
  • Respiratory disorders.
  • GI disorders.
  • Chronic pain.
• Many insomnia medications were studied in individuals without comorbidities.
• This has led to variable prescribing behaviours.

General Principles

• Use the lowest effective dose for the shortest duration.
• Follow up frequently (3–6 weeks).
• Dispense limited supplies (30–60 days).
• Ensure the underlying condition is adequately treated for those with comorbid insomnia.

Definitions

• Sedative: A drug that reduces excitement and calms the patient. Also called anxiolytics. They do not induce sleep.
• Hypnotic: A drug that results in drowsiness that promotes sleep.

Benzodiazepines

• GABA-A receptor agonists.
• Enhance chloride ion movement through GABA receptors.
• Enhance GABA channel effects and inhibition.
• Have sedative and hypnotic properties, but differ in potency and pharmacokinetics.
• Should only be used for short-term acute or intermittent insomnia.
• Long-term use should only be considered in severe or comorbid insomnia when other treatments have failed.
• Do not use multiple benzodiazepines (e.g., insomnia and anxiety).
• Do not combine with alcohol or other CNS depressants.

Benzodiazepine Properties (Table)

• *Officially indicated for insomnia in Canada.

Benzodiazepines - Further Considerations

• Flurazepam and nitrazepam are not recommended due to long half-lives.
• Triazolam is not recommended due to high risk of abuse, dependence, and rebound insomnia.
• Temazepam is suitable for those with Health Canada indications.

Adverse Effects of Benzodiazepines

• Dose-dependent ataxia, dizziness, dependence, withdrawal symptoms, impaired memory, risk of abuse.
• May cause dose-dependent next-day impairment, even if the patient feels fully awake.
• Use when there's a 7-8-hour period before awakening.
• Advise patients to wait at least 12 hours before driving or operating machinery.

Benzodiazepines - Use Duration

• Have been studied for up to 24 weeks.
• Rebound insomnia may occur after discontinuation.
• Deprescribing/gradual tapering over months may help.

Benzodiazepine Receptor Agonists (Z-Drugs)

• Allosteric modulators of GABA-A receptors.
• The presence of GABA does not facilitate action.
• Similar mechanism to benzodiazepines, where enhanced inhibition is caused via GABA-A receptors.

Z-Drugs - Benefits

• Generally the preferred class for treating insomnia.
• Similar effect on sleep to benzodiazepines.
• Fewer adverse effects.
• Less muscle relaxant effects.
• Do not worsen sleep apnea.
• Does not accumulate; less rebound on withdrawal.

Z-Drugs - Specifics

• Zopiclone is the most common Z-drug prescribed in Canada.

Adverse Effects of Z-Drugs

• Bitter/metallic taste, dry mouth, dizziness, somnolence.
• Complex sleep behaviours (night eating, somnambulism).
• May cause dose-dependent next-day impairment of activities requiring alertness (e.g., driving).
• Use only when there's a 7-8-hour period before planned awakening.
• Avoid combining with alcohol or other CNS depressants. Increased risk of complex sleep behaviours if combined with other CNS-active drugs.

Dual Orexin Antagonists

• Orexin/receptor pathways play vital regulatory roles (e.g., feeding behaviour, sleep-wake rhythm, reward, etc.).
• Neuropeptides in the hypothalamus promote arousal/wakefulness.
• Lemborexant is a competitive dual orexin antagonist.
• Normalizes sleep-wake function, reduces unwanted transitions.

Lemborexant -Further Considerations

• No evidence of withdrawal symptoms or rebound insomnia.
• Evidence supports efficacy for up to 12 months.
• Minimal next-day impairment.
• Minimal abuse potential.

Adverse Effects of Lemborexant

• Somnolence.
• Less commonly: sleep paralysis, hypnagogic/hypnopompic hallucinations, cataplexy-like symptoms.
• Complex sleep behaviours (night eating, somnambulism).
• May cause dose-dependent next-day impairment of activities requiring alertness (driving).
• Use only when there's a 7-8-hour period before planned awakening.
• Limited effects on driving impairment after 9 hours.
• Avoid combining with other CNS depressants.
• Contraindicated in narcolepsy.

Tricyclic Antidepressants (Doxepin)

• Selective histamine H1 receptor antagonist at low dosages.
• H1 receptors are associated with arousal and waking in the brain.
• Agonists promote wakefulness, antagonists promote sleep.

Doxepin -Further Considerations

• Indicated by Health Canada for sleep-maintenance difficulties.
• Trials support use for up to 3 months.
• May improve sleep maintenance better than GABA-A agonists.
• Not associated with rebound insomnia, dependence, or next-day impairment.
• Recommended treatment for the elderly.

Adverse Effects of Doxepin

• At low dosages, typical adverse effects are not seen.
• Somnolence, sedation, nausea may occur at higher doses..
• Should not be combined with alcohol or other CNS depressants.
• Should not be taken within 3 hours of food.

Off-Label Agents

• Many drugs causing sedation are sometimes used for conditions other than insomnia (off-label).
• Goal is to treat an underlying comorbidity while promoting sleep.
• Limited evidence for this practice.

Specific Examples of Off-Label Agents

• Insomnia with Centralized pain (e.g. fibromyalgia).
• Anticonvulsants (e.g. gabapentin).
• Conditions with allergy (e.g, eczema or allergies).
• Antihistamines.
• Insomnia and mood disorders.
• Antidepressants (sedating).

Insomnia and Children

• Non-pharmacological therapy generally recommended as first-line treatment.
• Limited evidence to guide use of medications.
• Over-the-counter antihistamines are not recommended, due to potential for rapid tolerance, next-day sedation, impaired cognitive function, and paradoxical reactions.
• Drugs should target the comorbidity.

Insomnia and the Elderly

• Prone to polypharmacy and drug interactions.
• Limit sedation-causing drugs to reduce fall risk.
• Recommend low-dose doxepin or Lemborexant
• Lemborexant suitable up to 6 months.

Insomnia and Pregnancy

• Disrupted sleep is a common complaint.
• Sleep apnea and restless leg syndrome can worsen during pregnancy.
• Little research on insomnia during pregnancy.
• No controlled studies of interventions in this population.
• Non-pharmacological options are generally first-line.
• Consider risk-benefit ratio for patients and developing fetus with pharmacologic interventions.
• Zopiclone can be a reasonable option. Avoid benzodiazepines particularly early in pregnancy

Case Studies (brief summaries)

• Case #1: 72-year-old with fatigue (frequent urination, potential hypertension/dyslipidemia).
• Case #2: 47-year-old with alcohol use disorder and daytime sleepiness (sleep disturbance history).

Case Study Considerations (brief examples)

• Case #1: Consider the patient's age, existing medications, potential medication interactions, and best drug option for insomnia.
• Case #2: Consider underlying diagnosis, type of insomnia, alcohol use considerations, and best treatment options.

This quiz covers the pharmacological treatments for insomnia, including their mechanisms of action, indications, and adverse effects. It examines various drug classes such as benzodiazepines, Z-drugs, and tricyclic antidepressants, as well as considerations for special populations like children and the elderly. Test your knowledge on effective insomnia therapies!